The cholinergic system has been implicated in memory, senility and central motor function. In Alzheimer's disease (AD), the most widely known example of central cholinergic pathology, evidence from biopsy and autopsy samples suggests that deficiencies in choline acetyltransferase (ChAT), acetylcholine (ACh) and (AChE) are among the earliest neurochemical changes in AD. Furthermore, cholinergic hypofunction is the most consistent neurochemical change associated with this disorder. Progress in the diagnosis and clinical management of AD has been hampered by the absence of reliable and specific methods of evaluating cholinergic function in patients with dementia. Consequently, the development of such methods may significantly improve the clinical management of AD. The goal of this project is to develop clinically useful positron- emitting radiotracers for evaluating cholinergic function in human neurological disorders with positron emission tomography (PET). In view of recent findings which suggest that the binding of radiolabelled vesamicol receptor (VR) ligands is responsive to the level of cholinergic activity in vivo, we postulate that suitably designed positron-emitting VR ligands may be uniquely suited to the diagnosis of human neurological disorders characterized by cholinergic dysfunction. Furthermore, these agents may find significant utility in monitoring the effectiveness of clinical measures (e.g. neural tissue grafts) designed to alleviate these conditions. To accomplish our goal, we propose to do the following: l) develop new positron-emitting VR ligands that are optimized for the evaluation of regional cholinergic function with PET, and which can be safely administered to humans; and 2) validate the use of radiolabelled VR ligands in measuring cholinergic function in vivo. Accordingly, a series of novel analogs of vesamicol, the prototypical VR ligand, will be synthesized and tested for binding to the VR in Torpedo synaptic vesicles and the sigma receptor (a frequent confounding factor in studies of vesamicol receptor ligands). To demonstrate the functional significance of VR ligand binding, selected analogues will also be evaluated for their ability to inhibit ACh transport in rat brain striatal and cortical synaptosomes. Those analogs which demonstrate a combination of high affinity and selectivity for the VR in the striatum and/or cortex, combined with moderate lipophilicity, will be radiolabelled and studied in rats and monkeys. In these studies, pharmacological manipulations (such as dopamine D2 and GABA receptor blockade) known to modulate cholinergic activity will be utilized as means of validating the use of VR ligands to study cholinergic function in vivo.